Targeting cholesterol homeostasis in hematopoietic malignancies

X Receptors

Cholesterol is a vital lipid for cellular functions. It is necessary for membrane biogenesis, cell proliferation and differentiation. In addition to maintaining cell integrity and permeability, increasing evidence indicates a strict link between cholesterol homeostasis, inflammation and haematological tumors. This makes cholesterol homeostasis an optimal therapeutic target for hematopoietic malignancies. Manipulating cholesterol homeostasis either interfering with its synthesis or activating the reverse cholesterol transport via the engagement of liver X receptors (LXRs), affects the integrity of tumor cells both in vitro and in vivo. Cholesterol homeostasis has also been manipulated to restore antitumor immune responses in preclinical models. These observations have prompted clinical trials in acute myeloid leukemia (AML) to test the combination of chemotherapy with drugs interfering with cholesterol synthesis, i.e. statins. We review the role of cholesterol homeostasis in hematopoietic malignancies, as well as in cells of the tumor microenvironment, and discuss the potential use of lipid modulators for therapeutic purposes.

Critical role of integrin CD11c in splenic dendritic cell capture of missing-self CD47 cells to induce adaptive immunity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1805542115 ◽

2018 ◽

Vol 115 (26) ◽

pp. 6786-6791 ◽

Cited By ~ 15

Author(s):

Jiaxi Wu ◽

Huaizhu Wu ◽

Jinping An ◽

Christie M. Ballantyne ◽

Jason G. Cyster

Keyword(s):

Critical Role ◽

T Cell Proliferation ◽

Cell Capture ◽

Antigen Uptake ◽

Missing Self

CD11c, also known as integrin alpha X, is the most widely used defining marker for dendritic cells (DCs). CD11c can bind complement iC3b and mediate phagocytosis in vitro, for which it is also referred to as complement receptor 4. However, the functions of this prominent marker protein in DCs, especially in vivo, remain poorly defined. Here, in the process of studying DC activation and immune responses induced by cells lacking self-CD47, we found that DC capture of CD47-deficient cells and DC activation was dependent on the integrin-signaling adaptor Talin1. Specifically, CD11c and its partner Itgb2 were required for DC capture of CD47-deficient cells. CD11b was not necessary for this process but could partially compensate in the absence of CD11c. Mice with DCs lacking Talin1, Itgb2, or CD11c were defective in supporting T-cell proliferation and differentiation induced by CD47-deficient cell associated antigen. These findings establish a critical role for CD11c in DC antigen uptake and activation in vivo. They may also contribute to understanding the functional mechanism of CD47-blockade therapies.

004.Control of skeletal muscle cell proliferation and differentiation

Reproduction Fertility and Development ◽

10.1071/srb05abs004 ◽

2005 ◽

Vol 17 (9) ◽

pp. 63

Author(s):

M. Grounds

Keyword(s):

Skeletal Muscle ◽

Cell Proliferation ◽

Multinucleated Cells ◽

The Matrix ◽

Key Issues

Skeletal muscle is formed by mononucleated precursor cells (myoblasts) that cease cell proliferation to start differentiation; this results in fusion between the myoblasts to form multinucleated cells (myotubes) that continue to differentiate (and fuse with more muscle cells) and mature into myofibres. Myogenesis has been widely used as a model to study in vitro factors controlling cell proliferation and differentiation. Condition in vitro may not reflect what happens in the more complex in vivo environment. Some of the key issues are what activates quiescent myoblasts in mature skeletal muscle in vivo, and what controls the switch between proliferation and differentiation? The role of the matrix, and molecules such as MyoD, p53, NFAT and IGF-1 will be considered.

Mechanics of the cellular microenvironment as perceived by cells in vivo

10.1101/2021.01.04.425259 ◽

2021 ◽

Author(s):

Alessandro Mongera ◽

Marie Pochitaloff ◽

Hannah J. Gustafson ◽

Georgina A. Stooke-Vaughan ◽

Payam Rowghanian ◽

...

Keyword(s):

Stress Relaxation ◽

Mechanical Parameters ◽

Cellular Microenvironment ◽

Stem Cell Maintenance ◽

Quantitative Studies ◽

3D Microenvironment ◽

Tissue morphogenesis and repair, as well as organ homeostasis, require cells to constantly monitor their 3D microenvironment and adapt their behaviors in response to local biochemical and mechanical cues1-6. In vitro studies have shown that substrate stiffness and stress relaxation are important mechanical parameters in the control of cell proliferation and differentiation, stem cell maintenance, cell migration 7-11, as well as tumor progression and metastasis12,13. Yet, the mechanical parameters of the microenvironment that cells perceive in vivo, within 3D tissues, remain unknown. In complex materials with strain- and time-dependent material properties, the perceived mechanical parameters depend both on the strain and timescales at which the material is mechanically probed14. Here, we quantify in vivo and in situ the mechanics of the cellular microenvironment that cells probe during vertebrate presomitic mesoderm (PSM) specification. By analyzing the magnitude and dynamics of endogenous, cell-generated strains, we show that individual cells preferentially probe the stiffness associated with deformations of the supracellular, foam-like tissue architecture. We reveal how stress relaxation leads to a perceived microenvironment stiffness that decreases over time, with cells probing the softest regime. While stress relaxation timescales are spatially uniform in the tissue, most mechanical parameters, including those probed by cells, vary along the anteroposterior axis, as mesodermal progenitors commit to different lineages. Understanding the mechanical parameters that cells probe in their native 3D environment is important for quantitative studies of mechanosensation in vivo2-4,6,15 and can help design scaffolds for tissue engineering applications16-18.

Notch Signaling Regulates MMP-13 Expression via Runx2 in Chondrocytes

Scientific Reports ◽

10.1038/s41598-019-52125-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Di Xiao ◽

Ruiye Bi ◽

Xianwen Liu ◽

Jie Mei ◽

Nan Jiang ◽

...

Keyword(s):

Notch Signaling ◽

Chondrocyte Proliferation ◽

Runx2 Expression ◽

Over Expression ◽

Important Regulator ◽

Signaling Activation

Abstract Notch signaling is involved in the early onset of osteoarthritis. The aim of this study was to investigate the role of Notch signaling changes during proliferation and differentiation of chondrocyte, and to testify the mechanism of MMP-13 regulation by Notch and Runx2 expression changes during osteoarthritis. In this study, Chondrocytes were isolated from rat knee cartilages. Notch signaling was activated/inhibited by Jagged-1/DAPT. Proliferative capacity of Chondrocytes was analyzed by CCK-8 staining and EdU labeling. ColX, Runx2 and MMP-13 expressions were analyzed as cell differentiation makers. Then, Runx2 gene expression was interfered using lentivirus transfection (RNAi) and was over-expressed by plasmids transfected siRNA in chondrocytes, and MMP-13 expression was analyzed after Jagged-1/DAPT treatment. In vivo, an intra-articular injection of shRunx2 lentivirus followed with Jagged1/DAPT treatments was performed in rats. MMP-13 expression in articular cartilage was detected by immunohistochemistry. Finally, MMP-13 expression changes were analyzed in chondrocytes under IL-1β stimulation. Our findings showed that, CCK-8 staining and EdU labeling revealed suppression of cell proliferation by Notch signaling activation after Jagged-1 treatment in chondrocytes. Promoted differentiation was also observed, characterized by increased expressions of Col X, MMP-13 and Runx2. Meanwhile, Sox9, aggrecan and Col II expressions were down-regulated. The opposite results were observed in Notch signaling inhibited cells by DAPT treatment. In addition, Runx2 RNAi significantly attenuated the ‘regulatory sensitivity’ of Notch signaling on MMP-13 expression both in vitro and in vivo. However, we found there wasn’t significant changes of this ‘regulatory sensitivity’ of Notch signaling after Runx2 over-expression. Under IL-1β circumstance, MMP-13 expression could be reduced by both DAPT treatment and Runx2 RNAi, while Runx2 interference also attenuated the ‘regulatory sensitivity’ of Notch in MMP-13 under IL-1β stimulation. In conclusion, Notch signaling is an important regulator on rat chondrocyte proliferation and differentiation, and this regulatory effect was partially mediated by proper Runx2 expression under both normal and IL-1β circumstances. In the meanwhile, DAPT treatment could effectively suppress expression of MMP-13 stimulated by IL-1 β.

Cell-intrinsic requirement for pRb in erythropoiesis

Blood ◽

10.1182/blood-2004-02-0618 ◽

2004 ◽

Vol 104 (5) ◽

pp. 1324-1326 ◽

Cited By ~ 42

Author(s):

Allison J. Clark ◽

Kathryn M. Doyle ◽

Patrick O. Humbert

Keyword(s):

Erythroid Differentiation ◽

Published Data ◽

Erythroid Cells ◽

Cell Cycle Exit ◽

A Cell ◽

Rb Gene

Abstract Retinoblastoma (Rb) and family members have been implicated as key regulators of cell proliferation and differentiation. In particular, accumulated data have suggested that the Rb gene product pRb is an important controller of erythroid differentiation. However, current published data are conflicting as to whether the role of pRb in erythroid cells is cell intrinsic or non–cell intrinsic. Here, we have made use of an in vitro erythroid differentiation culture system to determine the cell-intrinsic requirement for pRb in erythroid differentiation. We demonstrate that the loss of pRb function in primary differentiating erythroid cells results in impaired cell cycle exit and terminal differentiation. Furthermore, we have used coculture experiments to establish that this requirement is cell intrinsic. Together, these data unequivocally demonstrate that pRb is required in a cell-intrinsic manner for erythroid differentiation and provide clarification as to its role in erythropoiesis.

RhoGDIα-dependent balance between RhoA and RhoC is a key regulator of cancer cell tumorigenesis

Molecular Biology of the Cell ◽

10.1091/mbc.e11-01-0020 ◽

2011 ◽

Vol 22 (17) ◽

pp. 3263-3275 ◽

Cited By ~ 23

Author(s):

T. T. Giang Ho ◽

Audrey Stultiens ◽

Johanne Dubail ◽

Charles M. Lapière ◽

Betty V. Nusgens ◽

...

Keyword(s):

Tumor Growth ◽

Cancer Progression ◽

Dynamic Balance ◽

Cellular Functions ◽

Expression Of Genes ◽

Genes Encoding ◽

Interfering Rna

RhoGTPases are key signaling molecules regulating main cellular functions such as migration, proliferation, survival, and gene expression through interactions with various effectors. Within the RhoA-related subclass, RhoA and RhoC contribute to several steps of tumor growth, and the regulation of their expression affects cancer progression. Our aim is to investigate their respective contributions to the acquisition of an invasive phenotype by using models of reduced or forced expression. The silencing of RhoC, but not of RhoA, increased the expression of genes encoding tumor suppressors, such as nonsteroidal anti-inflammatory drug–activated gene 1 (NAG-1), and decreased migration and the anchorage-independent growth in vitro. In vivo, RhoC small interfering RNA (siRhoC) impaired tumor growth. Of interest, the simultaneous knockdown of RhoC and NAG-1 repressed most of the siRhoC-related effects, demonstrating the central role of NAG-1. In addition of being induced by RhoC silencing, NAG-1 was also largely up-regulated in cells overexpressing RhoA. The silencing of RhoGDP dissociation inhibitor α (RhoGDIα) and the overexpression of a RhoA mutant unable to bind RhoGDIα suggested that the effect of RhoC silencing is indirect and results from the up-regulation of the RhoA level through competition for RhoGDIα. This study demonstrates the dynamic balance inside the RhoGTPase network and illustrates its biological relevance in cancer progression.

The role of IGF1 on the differentiation of prolactin secreting cells in the mouse anterior pituitary

Journal of Endocrinology ◽

10.1677/joe-09-0232 ◽

2009 ◽

Vol 203 (2) ◽

pp. 231-240 ◽

Cited By ~ 13

Author(s):

Tamiki Hikake ◽

Shinji Hayashi ◽

Taisen Iguchi ◽

Tomomi Sato

Keyword(s):

Cell Proliferation ◽

Progenitor Cells ◽

Anterior Pituitary ◽

Cell Number ◽

Postnatal Period ◽

Gh Cells ◽

IGF1 knockout (IGF1KO) mice show a reduced number of prolactin (PRL) producing cells (PRL cells); however, the role of IGF1 in PRL cell proliferation and differentiation in immature mice is unclear. In this study, ontogenic changes in the percentages of PRL cells, GH producing cells (GH cells), and 5-bromo-2′-deoxyuridine (BrdU)-labeled cells in the anterior pituitary of male IGF1KO mice during the postnatal period were investigated. The percentage of PRL cells in IGF1KO mice was significantly lower at day 20 compared with that in wild-type (WT) mice, while GH cells in IGF1KO mice were significantly increased from day 10. From days 5 to 20, the percentage of BrdU-labeled cells in WT and IGF1KO mice was similar. PRL cells and GH cells are thought to originate from the same progenitor cells, therefore, PRL cells in IGF1KO mice are not able to differentiate because progenitor cells have already committed to be GH cells. However, IGF1, 17β-estradiol (E2), epidermal growth factor (EGF), or IGF1 plus E2 treatments increased the PRL cell number in the pituitaries in vitro of 10-day-old WT and IGF1KO mice. This fact suggests that these factors are involved in PRL cell proliferation and differentiation. In addition, the increase of PRL cells in IGF1KO mice stimulated by E2 or EGF was less than that of WT mice. Thus, IGF1 plays a crucial role in PRL cell proliferation and differentiation in mouse pituitaries by regulating the differentiation of progenitor cells and mediating the actions of E2 and EGF.

The role of progesterone in regulating human granulosa cell proliferation and differentiation in vitro.

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.76.3.8445028 ◽

1993 ◽

Vol 76 (3) ◽

pp. 696-700

Author(s):

L M Chaffkin ◽

A A Luciano ◽

J J Peluso

Keyword(s):

Cell Proliferation ◽

Granulosa Cell ◽

Human Granulosa Cell ◽

The Cdx-1 and Cdx-2 homeobox genes in the intestine

Biochemistry and Cell Biology ◽

10.1139/o99-001 ◽

1998 ◽

Vol 76 (6) ◽

pp. 957-969 ◽

Cited By ~ 60

Author(s):

Jean-Noël Freund ◽

Claire Domon-Dell ◽

Michèle Kedinger ◽

Isabelle Duluc

Keyword(s):

Cell Proliferation ◽

Ex Vivo ◽

Homeobox Genes ◽

Intestinal Cell ◽

Primary Role ◽

Colon Tumorigenesis ◽

The past years have witnessed an increasing number of reports relative to homeobox genes in endoderm-derived tissues. In this review, we focus on the caudal-related Cdx-1 and Cdx-2 homeobox genes to give an overview of the in vivo, in vitro, and ex vivo approaches that emphasize their primary role in intestinal development and in the control of intestinal cell proliferation, differentiation, and identity. The participation of these genes in colon tumorigenesis and their identification as important actors of the oncogenic process are also discussed.Key words: caudal, epithelial cell proliferation and differentiation, cancer.

In Vivo Interference with Skp1 Function Leads to Genetic Instability and Neoplastic Transformation

Molecular and Cellular Biology ◽

10.1128/mcb.22.23.8375-8387.2002 ◽

2002 ◽

Vol 22 (23) ◽

pp. 8375-8387 ◽

Cited By ~ 36

Author(s):

Roberto Piva ◽

Jian Liu ◽

Roberto Chiarle ◽

Antonello Podda ◽

Michele Pagano ◽

...

Keyword(s):

T Cell ◽

Cell Lineage ◽

Lymphoid Organ ◽

Cellular Functions ◽

Multinucleated Cells ◽

T Cell Lymphomas ◽

F Box Protein

ABSTRACT Skp1 is involved in a variety of crucial cellular functions, among which the best understood is the formation together with Cul1 of Skp1-cullin-F-box protein ubiquitin ligases. To investigate the role of Skp1, we generated transgenic (Tg) mice expressing a Cul1 deletion mutant (Cul1-N252) able to sequestrate and inactivate Skp1. In vivo interference with Skp1 function through expression of the Cul1-N252 mutant into the T-cell lineage results in lymphoid organ hypoplasia and reduced proliferation. Nonetheless, after a period of latency, Cul1-N252 Tg mice succumb to T-cell lymphomas with high penetrance (>80%). Both T-cell depletion and the neoplastic phenotype of Cul1-N252 Tg mice are largely rescued in Cul1-N252, Skp1 double-Tg mice, indicating that the effects of Cul1-N252 are due to a sequestration of the endogenous Skp1. Analysis of Cul1-N252 lymphomas demonstrates striking karyotype heterogeneity associated with c-myc amplification and c-Myc overexpression. We show that the in vitro expression of the Cul1-N252 mutant causes a pleiotrophic phenotype, which includes the formation of multinucleated cells, centrosome and mitotic spindle abnormalities, and impaired chromosome segregation. Our findings support a crucial role for Skp1 in proper chromosomal segregation, which is required for the maintenance of euploidy and suppression of transformation.